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EMERGENCY MEDICINE RESIDENCY CPC

Dyspnea and in a 45-Year-Old Woman

JONATHAN AMELI, MD; WILLIAM BINDER, MD

32 35 EN

From the Case Records of the Alpert Medical School of left and she has mild erythema overlying the skin bilaterally. Brown University Residency in Emergency Medicine DR. SARAH GAINES: The patient is tachycardic and hypoxic. DR. JONATHAN AMELI: Today’s patient is a 45-year-old What were your initial concerns and were you able to make woman who presents with difficulty and chest a diagnosis? pressure. Her chest discomfort has been constant since the morning. She had mild chest pain the day before, but ignored DR. AMELI: Our initial concerns included acute coronary it due to fear of visiting the emergency department (ED). syndrome, as well as (PE). Other dis- The patient has a history of bipolar disorder, morbid obe- orders on our differential diagnosis included COPD exacer- sity, and chronic obstructive pulmonary disease (COPD). bation, congestive failure, acute aortic dissection, and She smokes tobacco, occasional marijuana, and has a . An electrocardiogram was obtained within 10 long-standing . She is on aripiprazole, bronchodilators minutes of the patient’s arrival and she was found to have and inhaled steroids for COPD. a sinus tachycardia without significant ST abnormalities. A portable chest xray demonstrated a poor inspiratory effort DR. FRANCESCA BEAUDOIN: Can you describe her physical and non-specific bilateral air space disease. Laboratory stud- exam? ies revealed a WBC count of 18,000 mm3, an unremark- able chemistry panel, and a normal beta natriuretic peptide DR. AMELI: The patient is a morbidly obese woman in no (BNP) and troponin. A d-dimer was elevated at 2,777 ng/ml. distress. She is afebrile. Her pulse is 120 bpm and regular, A bedside echocardiogram showed no pericardial effusion, respiratory rate is 20, pressure is normal at 123/70 and the patient was stable enough to obtain a pulmonary mmHg, and she has an saturation of 85% on room embolism protocol CT scan. The CT demonstrated a large air. She has minimal wheezing on lung exam and her heart is pulmonary embolus at the right main pulmonary tachycardic with regular rhythm and no murmur. Her abdo- as well as multiple left sided segmental and subsegmental men is soft and non-tender, and she has bilateral edema in pulmonary emboli (figure 1). She also had likely pulmonary her lower extremities. Her right calf is slightly larger than the infarcts seen as ground-glass opacities bilaterally (figure 2).

Figure 1. Pulmonary Embolus at Right Main Pulmonary Artery Figure 2. Bilateral ground-glass opacities

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DR. JEFF FEDEN: The patient did not have any known on the clinical presentation in combination with biomark- risk factors for pulmonary embolism. How common is this ers, ECG findings, and echocardiogram abnormalities. Clot disorder? burden measured on CT has not been shown to be directly related to clinical manifestations and outcome – a morpho- DR. AMELI: Approximately 5%-8% of the US population logically extensive PE can present as a hemodynamically has one of several genetic risk factors leading to an increas- minor injury, while conversely a small PE can have signifi- ing risk of venous thromboembolism.1 Additionally, our cant hemodynamic consequences in patient’s with impaired patient had minor risk factors (relative risk = 2 – 4) includ- cardiovascular status and reserve.8,9 The American Heart ing obesity and chronic obstructive pulmonary disease, as Association (AHA) has defined 3 major risk categories in PE: well as tobacco use. Incidence of PE at age 45 is less than massive, submassive, and low risk.3 0.2% annually but rises significantly with age.2 There are Massive PE can be defined as sustained hypotension (sys- greater than 250,000 people hospitalized for PE per year.3 In tolic blood pressure <90 for at least 15 minutes), pulseless- the United States, approximately 100,000 deaths per year are ness, or sustained bradycardia (HR <40) with signs of shock, related to PE, with many cases not being diagnosed until and not due to another cause such as septic or hypovolemic autopsy, and 15% of all in-hospital deaths can be attributed shock.3 It is a morbid diagnosis. In the International Coop- to venous thromboembolism.4,5 erative Pulmonary Embolism Registry (ICOPER) trial, about half of the patients with acute PE and SBP<90 at presenta- DR. JOHN FOGGLE: This patient appeared to be hemody- tion died, and 15% of the remainder also succumbed during namically (HD) compromised. What is the pathophysiology their hospital stay. Additionally, having right ventricular of an acute PE that would cause her symptoms? (RV) hypokinesis, as measured by echocardiogram, doubled mortality.10 In the Management Strategies and Prognosis of DR. WILLIAM BINDER: The proximal portion of a lower Pulmonary Embolism (MAPPET) trial, which included 1,001 extremity deep venous thrombosis can break off sponta- patients, mortality during hospital stay occurred in 25% of neously, travel the venous system to the right ventricle, and patients with acute PE and HD instability, and in 65% of then lodge in the pulmonary . This obstruction can those requiring any form of CPR.11 cause an increase in dead space in the alveoli, leading to high Low-risk PE patients have HD stability on presentation, ventilation, low perfusion, and hypoxemia. normal biomarkers such as troponin and BNP, and no signs In a patient without prior cardiac or pulmonary disease, of RV dysfunction or strain on echocardiogram.3 obstruction of 30–50% of the pulmonary bed will lead to the A submassive PE is defined as a PE in a HD stable patient development of . The sudden higher with evidence of RV dysfunction as seen on ECG, biomarker pressures, in turn, leads to an increase in right ventricular levels, CT scan, or echocardiogram.3 On ECG, RV strain (RV) afterload, followed by RV dilatation and right-sided can be seen as the S1Q3T3 pattern, but more commonly, as .5,6 If pulmonary vascular resistance rises above a right bundle branch block, or t-wave inversions in leads a level the RV can tolerate, sudden death through pulseless V1-4.12 Biomarkers can be used to measure RV dysfunc- electrical activity or asystole can occur. In submassive PE, a tion caused by increased pulmonary vascular resistance. decrease in RV output causes diminished left ventricular (LV) Micro-infarctions and shear stress on the RV lead to eleva- filling, and interventricular septal bulging. Decreased out- tions in cardiac troponin and BNP. If a patient has normal flow leads to decreased blood pressure and syncope, or even biomarkers, and they are HD stable, it can be argued that an cardiogenic shock. Other complications include diminished echocardiogram is not needed to assess for RV dysfunction.13 coronary flow and subendocardial RV ischemia and infarc- If biomarkers are elevated with a confirmed PE, an echo- tion, which may be amplified by underlying coronary artery cardiogram is indicated for further risk stratification. RV dys- atherosclerosis. Because of dual pulmonary circulation aris- function on echocardiogram can be appreciated as dilatation ing from the pulmonary and bronchial arteries, pulmonary of the right ventricle (RV > LV more than 1:1), paradoxical infarction usually does not occur although it is certainly a septal motion (RV bows toward the LV via the interventricu- well known complication of pulmonary embolism.5 Com- lar septum), tricuspid regurgitation, or McConnell’s sign (RV pensatory mechanisms countering right-sided failure include free wall hypokinesis).14 The CT PE scan itself can be used to activation of the sympathetic nervous system and increased predict RV dysfunction by showing a right to left ventricular inotropy and chronotropy, which help preserve pulmonary ratio of >0.9.15 Findings of RV dysfunction in combination artery flow and maintain systemic circulation.5-7 with acute PE have been shown to be predictive of a higher odds-ratio of short-term mortality.16 DR. LISA MERCK: How do we risk-stratify PE once we have All three categories of confirmed or highly suspected pul- the diagnosis? monary embolism should be treated with supportive care, airway management, and in most cases, intravenous fluids DR. AMELI: Risk stratification has important manage- to increase preload. In addition, anticoagulation should be ment implications in pulmonary embolism, and is based started as soon as possible. Thrombolysis, in addition to

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heparin, should be used for all massive PE (SBP<90, HR<40, transferred to the medical floor, but she suddenly worsened cardiac arrest with high suspicion). Surgical embolectomy is and required intubation for hypoxic, hypercarbic respiratory considered in massive PE when there are absolute contrain- failure. She had a bronchoscopy that did not show evidence dications to thrombolysis.5 of infection. Her repeat echocardiogram showed mild RV dysfunction. Her biomarkers showed a small increase in DR. FRANZ GIBBS: Are thrombolytics indicated in sub- troponin and BNP. Thrombolytics were not used. After sev- massive pulmonary embolism? eral days on the ventilator, she was extubated, and had an uneventful course thereafter. She was again transferred to DR. AMELI: The decision to administer thrombolytics in the floor, and gradually weaned off oxygen. Her heparin drip submassive PE is controversial. Short-term mortality in was bridged to warfarin, and she was discharged successfully submassive PE is approximately 3%, and development of a few days later. pulmonary hypertension occurs in 0.1 – 3.8% of patients. Consequently, many studies are not sufficiently powered DIAGNOSIS: Submassive PE in an obese patient with COPD. to evaluate composite endpoints.9 While the Pulmonary Embolism Thrombolysis (PEITHO) trial demonstrated improvement in HD in submassive PE through fibrinoly- References sis with tenecteplase, the risk of major bleeding was sig- 1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous nificant.17 The Tenecteplase or Placebo: Cardiopulmonary thromboembolism: a public health concern. Am J Prev Med. 2010 Apr;38(4 Suppl):S495-501. Outcomes at Three Months (TOPCOAT) trial showed that 2. Cushman M. Epidemiology and Risk Factors for Venous Throm- treatment with tenecteplase in combination with heparin boembolism. Seminars in Hematology. 2007;44:62–69. in submassive PE was associated with positive self-assess- 3. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, ment of health (such as exertional dyspnea, exercise toler- et al. Management of massive and submassive pulmonary em- bolism, iliofemoral , and chronic thrombo- ance) at 90 days by the surviving patients as compared to embolic pulmonary hypertension: a scientific statement from those that received heparin alone. Limitations to this trial the American Heart Association. Circulation. 2011;123:1788- include an early termination, and a small sample size.18 The 1830. Moderate Pulmonary Embolism Treated with Thrombolysis 4. Konstantinides S. Acute Pulmonary Embolism. N Engl J Med. 2008;359:2804-2813. (MOPETT) trial showed half-dose tPA in combination with 5. Tapson V. Acute Pulmonary Embolism. N Engl J Med. enoxaparin for submassive PE was effective in decreasing 2008;358:1037–1057. pulmonary hypertension and recurrent PE at 28 months in 6. Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part comparison to enoxaparin alone. However, limitations of II: Management. Exp Clin Cardiol. 2013;18:139-147. this study included lack of blinding among other issues.19 7. James AH. Venous Thromboembolism: Mechanism, Treatment and Public Awareness. Arteriosclerosis, Thrombosis and Vascu- Catheter-directed embolectomy is another alternative lar Biology. 2009;29:326– 331. method designed to reduce the systemic effects of throm- 8. Kirchner J, Obermann A, Stückradt S et al. Lung Infarction Fol- bolysis. While it has been shown to increase RV function lowing Pulmonary Embolism: A Comparative Study on Clinical in submassive PE, it has not yet demonstrated efficacy Conditions and CT Findings to Identify Predisposing Factors. Fortschr Röntgenstr. 2015; 187: 440 - 444. in decreasing ICU length of stay, or improving patient 9. Ain DL, Jaff MR. Treatment of Submassive Pulmonary Embo- outcomes. 20,21 lism: Knowing when to be Aggressive and When to be conserva- There still does not exist a single, large trial that shows tive. Current Treatment Options in Cardiovascular Medicine. 2015;17:385-394. thrombolysis, in addition to standard anticoagulation for 10. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embo- submassive PE, is beneficial in terms of all-cause mortal- lism: clinical outcomes in the International Cooperative Pul- ity, although a meta-analysis in JAMA has shown some monary Embolism Registry (ICOPER). Lancet. 1999;353:1386- benefit.22 The AHA has consistently recommended throm- 1389. bolytics to be used only for massive PE.3 The most recent 11. Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, et al. Management strategies and determinants of outcome American College of Emergency Physicians (ACEP) clinical in acute major pulmonary embolism: results of a multicenter policy from 2011 states that thrombolytics should only be registry. J Am Coll Cardiol. 1997;30:1165-1171. used in massive PE, or HD unstable patients with confirmed 12. Goldhaber SZ. Thrombolysis for pulmonary embolism. N Engl J Med. 2002; 347:1131-1132. pulmonary embolism (level B recommendation), or massive 23 13. Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratifica- PE with high suspicion (level C recommendation). tion of patients with acute pulmonary embolism. Circulation. 2003;108: 2191-2194. DR. ERIC GOLDLUST: What was the patient’s clinical course 14. Dresden S, Mitchell P, Rahimi L, Leo M, Rubin-Smith J, et al. and outcome? Right ventricular dilatation on bedside echocardiography per- formed by emergency physicians aids in the diagnosis of pulmo- nary embolism. Ann Emerg Med. 2014; 63:16-24. DR. AMELI: In the ED, she was immediately started on a 15. Sanchez O, Planquette B, Roux A, Gosset-Woimant M, Meyer heparin drip, and admitted to the medical intensive care unit G. Triaging in pulmonary embolism. Semin Respir Crit Care Med. 2012;33:156-162. (MICU). After a very brief stay in the MICU, the patient was

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16. Sanchez O, Trinquart L, Caille V, Couturaud F, Pacouret G, et Authors al. Prognostic factors for pulmonary embolism: the prep study, Jonathan Ameli, MD, PGY-3. Brown University Residency in a prospective multicenter cohort study. Am J Respir Crit Care Emergency Medicine Med. 2010;181:168-173. 17. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, et al. Fi- William Binder, MD, Associate Professor of Emergency Medicine. brinolysis for patients with intermediate-risk pulmonary embo- Alpert Medical School of Brown University. lism. N Engl J Med. 2014;370:1402-1411. 18. Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Correspondence Rose GA. Prospective evaluation of right ventricular function William Binder, MD and functional status 6 months after acute submassive pulmo- [email protected] nary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. 2009;136:1202- 1210. 19. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moder- ate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111:273-277. 20. Piazza G, Goldhaber SZ. Acute pulmonary embolism: part II: treatment and prophylaxis. Circulation. 2006;114: e42-7. 21. George B, Wallace EL, Charnigo R, Wingerter KE, Kapadia P, et al. A retrospective analysis of catheter-based thrombolytic ther- apy for acute submassive and massive pulmonary embolism. Vasc Med. 2015;20:121-130. 22. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, et al. Thrombolysis for pulmonary embolism and risk of all- cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311: 2414-2421. 23. Fesmire FM, Brown MD, Espinosa JA, Shih RD, Silvers SM, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspect- ed pulmonary embolism. Ann Emerg Med. 2011;57:628-652.e75.

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